Vapor phase synthesis of carbon-substituted pyrazines and piperazines



V APOR PHASE SYN JtHESIS OF CARBON-SUBSTI- TUTED PYRAZWES ANDPlPERAZlNES William K. Langdon, Grosse Ile, Mich., assignor to WyandotteChemicals Corporation, Wyandotte, Mich a corpartition of Michigan NoDrawing. Application March 29, 1957, Serial No. 649,311

9 Claims. (Cl. 260-268) This invention relates to the synthesis ofcarbon-substituted pyrazines and piperazines. In a more specific aspect,

. this invention relates to an improved method of synthesizingcarbon-substituted pyrazines and piperazines which is conducted in vaporphase over a copper hydrogenation/ dehydrogenation catalyst.

This application is a continuation-in-part of my copending applicationSerial No. 432,686, filed May 27, 1954, now abandoned.

Carbon-substituted pyrazines and piperazines, such as2,5-dimethylpyrazine, 2,5-dimethylpiperazine, 2,5-diethylpyrazine and2,5-diethylpiperazine, are known compounds whose chemical and physicalproperties make them of interest as intermediates in the preparation ofrubber accelerators, condensation polymers, pharmaceuticals anddyestuffs. In spite of their many interesting chemical and physicalproperties, such compounds have heretofore been little more thanlaboratory curiosities because they have been obtainable only throughdifficult and costly synthesis. Typical of the syntheses used to obtain2,5-dimethylpiperazine are the following:

(A) Reduction of 3,6-dimethyl-2,5-diketopiperazine with sodium (Hoyer,Z. physiol. Chem., 34, 350 (1902)).

(B) Reduction of 2,5-dimethylpyrazine with sodium (Stoehr, J. prakt.Chem. (2) 47, 494, 508 (1893)).

(C) Catalytic hydrogenation of lactamide over copper chromite (Oeda, J.Chem. Soc. Japan, 13, 465-70 (1938); Chemical Abstracts, 32, 8427(1938)).

All of the above methods sutt'er the shortcoming of requiring costly rawmaterials or giving poor yields or both. Bain and Pollard have disclosedin the Journal of the American Chemical Society, vol. 61, page 532(1939), that isopropanolarnine was heated in liquid phase in a dioxanesolution over a copper chromite catalyst at 250- 275 C. and an 18% yieldof 2,5-dimethylpiperazine was obtained. Although the Journal articlecited above does not give the complete reaction conditions employed byBain and Pollard, page 43, of the original thesis from which the digestwas made makes it clear that the reaction by Bain and Pollard wascarried out in dioxane solvent in liquid phase in a bomb reactor. Ayield of 18% is obviously inadequate as a basis for a profitablecommercial application of the method.

It is an object of this invention, therefore, to provide an improvedmethod for preparing carbon-substituted pyrazines and piperazines.

It is a further object of this invention to provide an ellicient andeconomical synthesis for carbon-substituted pyrazines in high yield.

I have found that carbon-substituted pyrazines and piperazines can beprepared in high yields by heating an alkanolamine, subsequentlydefined, in the presence of a copper hydrogenation/dehydrogenationcatalyst in the vapor phase at a temperature in the range from 175-4002,813,869 Patented Nov. 19, 1957 2 C. The alkanolamines employed in theprocess of this invention correspond to the formula wherein R is amethyl or ethyl radical and R is hydrogen. or a methyl radical, thetotal number of carbon atoms in R and R collectively being not greaterthan 2. Thus, the alkanolamines employed in the process aremonoisopropanolamine, 1-amino-2-hydroxybutane and 2-amino-3-hydroxybutane. When monoisopropanolamine is employed in the process ofthe invention, the product is predominantly 2,5-dimethylpyrazinetogether with a minor quantity of 2,5-dimethylpiperazine. When l-amino-2-hydroxybu'tane is employed in the process, the product is mainly2,5-diethylpyrazine together with a minor amount of2,5-diethylpiperazine. When the alkanolamine employed in the process is2-amino-3-hydroxybutane, the product obtained is2,3,5,6-tetramethylpyrazine together with a small quantity of2,3,5,6-tetramethylpiperazine.

The most significant factor in the process of this invention is thatconversions of over 50% to the carbonsubstituted pyrazines andpiperazines are obtained predominating largely in the carbon-substitutedpyrazine product. While the reaction mechanism has not been definitelyand unequivocally established, it is belived that the process does notproceed through a simple intermolecular dehydration between an aminohydrogen atom and the hydroxy group of the alkanolamine. There isevidence that two or more competing reaction mechanisms are involved,each of which proceeds through a series of intermediate reactions. Theprocess is believed to proceed through a series of steps involvingdehydrogenation, hydrogenation and both intermolecular andintramolecular Schilf base formations, i. e., a dehydration between aprimary amine and aketone.

Any of the well-known copper hydrogenation/dehydrogenation catalysts canbe used in the process of this invention. Particularly outstandingresults have been obtained with copper chromite and this catalystconstitutes a preferred catalyst in the process of the invention.However, other copper hydrogenation/dehydrogenation catalysts have beenused successfully in the process of the invention, such as copper metalturnings, barium-stabilized copper chromite on silicate support, andmetallic copper on an alumina support.

The process of this invention can be carried out over a wide range oftemperatures, the precise range being determined by such variables asthe particular copper catalyst employed, its activity, the contact timebetween the alkanolamine and the catalyst, and the yield and conversiondesired. In particular, the type of copper catalyst and its activity hasa very important influence on the temperature employed in the process.For example, with 9 the thermal decomposition of the carbon-substitutedpyrazines and pyrazines produced by the process of this invent1on, it ispossibleto'operate attemperatures as high as 400C. or even higherWithout substantially adversely af-I fecting the total yield andconversion. The temperature employed generally falls in the range from175 C. to about 400 C. Generally optimum conversions and yieldsareobtained at a temperature in the range from about 225 C. to about 350C., with the very best results usually bcing obtained within thetemperature range of about 250 C. to about 325 C.

The effect of the contact time between the alkanolamine and the catalyston the temperature range is that which would be expected. With shortcontact times, higher temperatures can be employed than when longercontact times are used; Similarly, at lower temperatures it is possibleto obtain better yields and conversions with long contact times thanwhen shorter contact times are used; Other process variables such as theuse of inert diluents also have at least a minor effect upon thetemperature than can be employed.

The, reaction can be carried out at either atmospheric or subatmosphericpressures. This invention is concerned solely with a vapor phasereaction and for this reason it is not feasible to operate at pressuressubstantially above atmospheric, since such pressures cause liquefactionof the alkanolamine reactant.

It has been noted that the process of this invention producescarbon-substituted pyrazines and piperazines. The ratio of suchpyrazines to such piperazines that is obtained is importantly influencedby the reaction conditions employed. The formation of carbon-substitutedpyrazines is favored by high temperatures and long contact times whereascarbon-substituted piperazines are favored by low temperatures and shortcontact times. A fundamental feature of the process of this inventionresides in the production of proportionately large amounts ofcarbon-substituted pyrazines.

Theoretical considerations would indicate that the ad'- dition ofhydrogen to the alkanolamine feed would favor the formation of thecorresponding carbon-substituted piperazines and this result has beenobserved experimentally. However, the addition of hydrogen to thereaction also lowers the total conversion of the desired carbonsubstituted pyrazines and piperazines, and as a result, wherecarbonesubstituted piperazines are desired, it is better practice tocarry out the processin the absence of added hydrogen and subsequentlyhydrogenate the carbon-substituted pyrazineina separate step. Wherecarbon substituted pyrazines are desired as the sole product, theco-formed carbon-substituted piperazines can be recycled. to. thereaction zone and dehydrogenated in the process of. the reaction.

The total reaction product obtained in the process ofthe invention is amixture consisting predominantly of Water, carbon-substituted pyrazinesand carbon-substituted piperazines and unreacted alkanolamine. Thecarbonsubstitutedpyrazines can be easily removed from the reactionmixture by simply adding water thereto, if needed, and distillingtherefrom an azeotrope of carbonsubstitutedpyrazine and water. Thecarbon-substituted piperazine can be separated'from the reaction mixtureby fractional distillation. In the case where monoisopropanoiamine isempioyed in the process of the invention, the: unreactedmonoisopropanolamine can be separated from the 2,5-dimethylpiperazineproduct by azeotropic distillation with xylene, ethylbenzene orisopropylbenzene as disclosed and claimed in the copending applicationof John T. Patton, In, Serial No. 562,941, filedFebruary 2, 1956.

The following examples are set forthto illustrate the principle andpractice of the process of this invention and should not be employed tounduly restrict the scopeof the process as it has beendisclosed-hereinabove. The terms conversion. and yield are employed inthis specification and are defined as follows:

(2)X (mols product. obtained) X (100) Percent weld: (mols alkanolamine(mols alkanolamine charged) recovered) EXAMPLE 1 The reactor employed inthis example and Examples 2 and 3 was a section of 18 mm. 1. D. glasstubing packed to a depth of approximately 24 inches with catalyst. Thecatalyst employed was metallic copper on an alumina support (Harshaw Cu0801, Harshaw Chemical Company, Cleveland, Ohio). Before the reactionwas run, the catalyst bed was conditioned by sweeping the system free ofair with hydrogen and heating to C. The catalyst bed was then heated to275 C. and monoisopropanolamine was fedthrough the catalyst zone for aperiod of 3.2 hours at a rate of 0.42 gram of monoisopropanolamine perhour per gram of catalyst. The yield and conversion that were obtainedare shown in Table I.

Table I Reaction temperature C-.. 275 Conversion to DMPy 1 percent 42Conversion to DMP 2 do 8 Total conversion to DMPy and DMP do 50 Totalyield of DMPy and DMP do 66 1 2,5-dimethylpyrazine.

- 2 2,5-dimethylpiperazine.

EXAMPLE 2 The process of theinvention employed in Example 1 was repeatedusing difierent copper catalysts. The alkanolamine employed wasmonoisopropanolamine and the catalystsemployed in runs Nos. 1 and 2 werecommercial copper dehydrogenation catalysts. The catalyst employed inrun No. 3 was turnings of reagent grade electrolytic copper. Theconditions under which these runs were carried out and the conversionand yield data are set forth below in Table II.

1 2,5-dimethylpyrazine.

2 2,5-dimethylpiperazine. Harshaw Cu 0203; Harshaw Chemical Company,Cleveland, Ohio. b Harshaw Cu 1107, Harsbaw Chemical Company, Cleveland,Ohio. Bakerandndamson reagent grade electrolytic copper.

The runs carried out in Examples 1 and 2 demonstrate clearly the highconversion to carbon-substituted pyrazines a-nd' carbon-substitutedpiperazines that are obtained in the process of this invention. Thetotal conversions when commercial copper hydrogenation catalysts wereused'ranged frorn 64 to 74 weight percent.

high proportion of carbon-substituted pyrazines obtained in the productsof the process, e. g., 66% in run No. l where the total conversion was74%.

EXAMPLE 3 The effect of temperature upon the yield, conversion andproduct distributionis illustrated by the data in Table III. below whichwere obtained by passing monoisopro- 7 panolamine over the copperchromite catalyst of run No.

An extremely important feature of the process of this invention is the1, Example 2, at the rate of 0.5 gram of monoisopropanolamine per hourper gram of catalyst at temperatures of 200, 225, 250 and 275 C.

Table 111 Temperature, C 200 225 250 275 Conversion to DMPy 1 30. 6 36.6 49. 2 66. 1 Conversion to DMP 2 23.9 19. 3 16.1 7. 8 Total Conversionto DMPy and DMP 54. 5 55. 9 65. 3 73. 9 Total Yield of DMPy and DMP 64.8 65.8 69. 3 75. 2

EXAMPLE 4 A run was carried out to prepare diethylpyrazine anddiethylpiperazine in the process of the invention. The alkanolamineemployed was the reaction product of butylene oxide and ammonia. Thebutylene oxide employed was butylene oxide S supplied by The DowChemical Company which is a mixture of butylene oxides containing about90% of l-butene oxide and 5% each of cis and trans Z-butene oxide. Thus,the alkanolamine employed was a mixture containing predominantly 1-amino-2-hydroxybutane and a small amount of 2-amino- 3-hydroxybutane.The reaction of l-amino-Z-hydroxybutane in the process of the inventionprovides a mixture of 2,5-diethylpyrazine and a small amount of2,5-diethylpiperazine. The reaction of 2-amino-3-hydroxybutane in theprocess of the invention produces a product mixture containing 2,3,5,6tetramethylpyrazine and a small amount of 2,3,5,6-tetramethylpiperazine.Also, intermolecular cyclodehydration between the two types ofbutanolamines results in the formation of a small amount of2,3-dimethyl-5-ethylpyrazine and 2,3-dimethyl-5-ethylpiperazine. Due tothe large predominance of l-butene oxide in the oxide mixture employedin preparing the butanolamine reactant, the product of this run waslargely 2,5-diethylpyrazine.

The run was carried out by trickling the butanolamine reactantdownwardly through a reactor tube containing copper chromite catalyst(Harshaw Chemical Company Cu 0203). The reactor was a 1-inch I. D.stainless steel tube encased in an electrically heated core furnace. Thecatalyst occupied a space of 24 inches within the steel tube, weighed671 grams and was preceded by 19% inches of inert packing, which servedto preheat and vaporize the butanolamine reactant.

The catalyst was prepared for the run by heating it up to 250 C. andflowing hydrogen over the heated catalyst. The feed of the butanolaminereactant was started at a rate of about 260-270 grams per hour. Thereaction temperature employed was about 200 C. A total of 1506 grams(16.9 mols) of the butanolamine was passed over the catalyst during asix-hour period. The weight of liquid eflluent from the reactor was 1404grams. The 1404 grams of crude product was azeotropically distilled 6with water, the distillate salted out with caustic soda and the oillayer redistilled.

The distillation of the product showed that a 63.2% conversion tocarbon-substituted pyrazines was obtained and that the pyrazine productwas largely 2,5-diethylpyrazine. There was a 1.1% conversion tocarbon-substituted piperazines and the main piperazine product was2,5-diethylpiperazine.

It will be noted that high conversions to carbon-substituted pyrazinesand, carbon-substituted piperazines are obtained in the process of thisinvention. The remarkably improved conversions obtained in the vaporphase process of this invention employing a copper hydrogenation/dehydrogenation catalyst are suflicient to render this process adaptableto commercial applications. Broadly speaking, my process is a method ofpreparing carbonsubstituted pyrazines and carbon-substituted piperazinesby heating an alkanolamine in the presence of a copperhydrogenation/dehydrogenation catalyst in the vapor phase at atemperature in the range of -400 C.

I claim:

1. A method for preparing carbon-substituted pyra zines,carbon-substituted piperazines and mixtures thereof, which comprises,heating an alkanolamine in the presence of a copper hydrogenation/dehydrogenation catalyst in the vapor phase at a temperature in therange from 175-400" C., said alkanolamine corresponding to the formulawherein R is a member selected from the group consisting of methyl andethyl radicals, R is a member selected from the group consisting ofhydrogen and a methyl radical, the total number of carbon atoms in R andR collectively being not greater than 2.

2. A method according to claim 1 wherein said alkanolamine ismonoisopropanolamine.

3. A method according to claim 1 wherein said alkanolamine isl-amino-Z-hydroxybutane.

4. A method according to claim 1 wherein said alkanolamine is2-amino-3-hydroxybutane.

5. A method according to claim 1 wherein said copper catalyst is copperchromite.

6. A method for preparing 2,5-dimethylpyrazine, 2,5- dimethylpiperazineand mixtures thereof, which comprises, heating monoisopropanolamine inthe presence of a copper chromite hydrogenation/dehydrogenation catalyst in the vapor phase to a temperature in the range from 225350 C.

7. A method according to claim 5 wherein said temperature is in therange of 250-325 C.

8. A method for preparing 2,5 diethylpyrazine, 2,5-diethylpiperazine andmixtures thereof, which comprises, heating l-amino-Z-hydroxybutane inthe presence of a copper chromite hydrogenation/dehydrogenation catalystin the vapor phase to a temperature in the range from 225-350 C.

9. A method according to claim 7 wherein said temperature is in therange from 250325 C.

No references cited.

1. A METHOD FOR THE PREPARING CARBON-SUBSTITUTED PYRAZINES,CARBON-SUBSTITUTED PIPERAZINES AND MIXTURES THEREOF, WHICH COMPRISES,HEATING AN ALKANOLAMINE IN THE PRESENCE OF A COPPERHYDROGENATION/DEHYDROGENATION CATALYST IN THE VAPOR PHASE AT ATEMPERATURE IN THE RANGE FROM 175-400*C., SAID ALKANOLAMINECORRESPONDING TO THE FORMULA